Conditionally Activatable Chimeras for Tumor-Specific Membrane Protein Degradation
Hongxiang Liu, Zhijiang Fu, Yu Han, Yike Fang, Weijun Shen, Zhicheng Chen, Rongfeng Zhu, Heng Zhang, Peng R. Chen
Abstract
The recent advancements on membrane protein degraders (MPDs) have broadened the applicability of proteolysis-targeting chimeras (PROTACs) beyond intracellular proteins to include the previously “undruggable” cell-surface targets. However, the potential toxicity of MPDs caused by undesired off-target degradation poses a significant challenge to clinical deployment, mirroring concerns associated with PROTACs. Here, we introduce a conditionally activatable membrane protein degrader (Pro-MPD), which leverages the specificity and high affinity of biparatopic nanobodies combined with a tumor microenvironment-activated cell-penetrating peptide (Pro-CPP) to achieve on-target activated internalization and degradation of PD-L1 within tumor sites. This modularly designed Pro-MPD demonstrated a high target degradation efficiency and T cell reactivation, as well as sustained inhibition of tumor growth in xenograft models, highlighting its potential as a safer and highly efficient MPD for in vivo applications. Our work provides a general strategy for the development of conditionally activatable MPDs, which offers a new avenue for reducing the undesired systemic toxicity of MPDs due to the off-tumor degradation.